Disubstituted glycyl derivatives of amino quinolines



Patented Jan. 10, 1950 DISUBSTITUTEUGLYCYL DERIVATIVES- F ALMINW QUINOLINES e William- F.;B1:uce, Ilpper Darby, Pa assignor to wyeth lncorpprated, Philadelphia;-Pa;;- a-'co1"-" poration'otDelalware No Drawings ApplicatiomAprikl'I, 1945;

Serial No. 588,885

This invention relates in general to the synthesis of new-chemicalrcompoundsxof .theouino line series, and'in"particulan'relatesto the'syn thesis of quinoline compounds in which a disubstituted glycyl radical (-COCH2NRR) is attached through an amino groupzonrbr-idge stosa carbon atom ofan ialkoxys substituted quinoline ring. represented by "the formula" QNHCO'CI-IzNRR' wherein Q is analkoxy substituted :quirioline ring and R and R are hydrocarbomradicals :such as alkyl, aryl, aralk'yl orcycloalkyrgroups;idrin= stance, methyl, ethyl? propyl, b'uty'lf phenyL.

benzyl, cyclopentyl and cyclohexyl'f radicals T01 NRR" together constitute a' hetero'cycli'c ring. R and R maybe similar 'or" dissimilar. These compounds :are useful as "spasm'olytic "andlocal anesthetic agents.

The preferred embodiment of my invention is directed to the synthesis'of the more specific group of compoundsrepresentedrbymhe generic formula g NT, BL.

wherein R,- R" and R" 'are alkyl;aryrbrcycldal; kylradicals which may "-be 'similar "or di'ssimllar or wherein Structurally,\..such compounds can be:

stirring, a solutionroi 126 cc. (40gms.) of chloracetyle chloride-dissolved in 250* cc. of ether. Slow additioniand coolingrwas necessary as the reaction wasinstantaneous andviolent. After addition. of the chloracetyl chloride and vigorous stirringidr some time. the precipitated solid hydrochloride of the: reaction product was filtered ofi-Ilsuspended in ether. andv refilteredt. The filtrate was found to contain a small amount of unreacted aminoquinolinei The yield of impure hydrochloride was 95 gms. or 95% of the theoretical. After recrystallizationfrom alcohol, the product melted at 240 to 241 C. The B-methoxy 8- (alpha chloracetamido) -quinoline hydrochloride gave the following analysis:

Calculated IOIYCHHnNiOQ OIHCI 50. 2% C 4. 18% H Found -49. 8% 4. 41% 50. 4% 4. 35%

The '-fre'e-base-was readily prepared from; the hydrochloride" -byitreatment with" sodium hydroxide' or-sodium carbonate and was purified by crystallization from benzene: The "purified base h'adameltihgpoint bf '11'0-to 111 C.

Analysis:-

Orlloula'tedfor:T-CiaHiiNECMOLLo .-57ts4%,0 4. 4 H 14.18% 11.18% Fo 83% 4. 46%

Analysis alcllldtedifoli cinHzfiNaoi -70."0%'C Preparatibn' of" 6methbxy-'8 (alphacliethyl 'am'inoacetamz'do) quin'oline J 45 of .-6-methoxyi- 8- (alphachloracetami- .do) -quinoline (23:5lgmsvor a 2-mol ratio) of diethylamine were refluxed with 300 cc, of .prcpyl alcohol for ldhoursa The reaction-solution was concentrated under vacuum to a small volume and then diluted with volumes of ether to give a precipitate of cliethylamine hydrochloride which was filtered off. After evaporating the ether from the filtrate, an oily residue remained which was distilled under vacuo. The yield of G-methoxy- 8 (alpha diethylaminoacetaniido) quinoline which boils at 260 to 263 at mm. amounted to 50 gms.

Analysis Calculated for: CmHmNsOg 67. 0% C 7. 32% H Found 82% 1.56%

EXAMPLE in aminoacetamiclo) -qninoline 45 gms. of 6-methoXy-8-(alpha-chloracetamia i.

Analysis Calculated for: CZOHEJNSOQ "70 0% O 8. H Found 70. 31% 8. 80%

EXABEPLE VI Preparation of 6-methoxy-8-(alpha-di-n-amylaminoc cetamiclo) -quinoline gms! of G-inethoXy-S-(alpha-chloracetamido) -quinoline and cc. (57 gms.) of di-n-amylamine were refluxed with about 300 cc. of propyl alcohol for about sixteen hours. The reaction sodo) -quinoline and 52 cc. (38 gms.) of diisopropylamine were refluxed in 390 cc. propyl alcohol for a period of about sixteen hours. Vacuum evapo- Analysis Calculated for: OoHisNw-z 53. 55% G 7. 95% H Found 138. 45% 7. 99%

EXAlVlrLE IV Preparation of 6-metlzoxy-8 (alpha-di-n-p1opylaminoacetamido) quinoline 45 gms of 6-methoxy-8-(alpha-chloracetaini- .do)-quinoline were refluxed in 300 cc. of propyl l alcohol with 52 cc. (38 eras.) of dinpropyla rnine for about sixteen hours. The reaction solution was concentrated to a small volume under vacuum and then was diluted with ten volumes of ether to precipitate out cli-n-propylamine hydrochloride. An oily residue was secured upon. evapo rating oil the solvent from the filtrate. The oily residue was distilled under Vacuum to give 5%) girls. of oily B-methoXy-S-(alphafli-n-propylaminoacetamido) -quinoline having a boiling point of 236 to 237 at 35 mm.

Analysis Calculated for: OlBHlSNBO'l 7. 95% H Found 8.21%

EXAMPLE V Preparation of G-methozry-S (alpha-diisobntylaminoacetamz'do) -qulnoline F Preparation of fi-methoxy-S (alplzri diisopropyl l lution wasooncentrated under vacuum to a small volume and then diluted with ten volumes of ether to precipitate out di-n-amylamine hydro- "BllIOIldl The solvent was evaporated from the filtrate and the thus obtained oily residue was .l 'distilled under vacuo to give 51 girls, of S-methoxy-8e (aipha-di n-amylaminoacetamido) -quinoline having a boiling point of 308 to 310 C. at 33 min. a

Analysis Oalculatedfor: caesium-" 7s. 5%0 Found 74.l1

EZZAMPLE VII Preparation of 6rnethoa:y-8 -(alpha-piperidylacciar/n'clo) quz'noline lilo cc. of piperidine and 45' gmsofG-methoxy- 8-(alpha-chloracetamido)-quino1ine were reliuxed with about 300 cc. of propyl alcohol for about sixteen hours. After removing piperidine hydrochloride by the ether treatment described in the examples, and after driving off the solvent from the ethereal filtrate under vacuum, an oily residue was obtained. Upon vacuum distillation, 69 arms. or G-meth'oxy-S-(alpha-piperidylacetamido) quirioline, boilingpoint 273 to 276 at 35 mm., was secured. v

"Analysis Calculated fDl'Z-CITHMNRO'J .68. 25% C 7. 03% H Found G8. 53% I 7. 30%

By procedures analogous to those described in the above examples using the appropriate allroziy (alpha haloge no aoetamido) quinoline and the appropriate secondary amine, the following substituted quinolines representative of those visualized in this invention may be prepared: v

(l) 5 methoxy-8-(alpha-diethylaminoacetamido) -quinoline.

(2) G-ethoxy 8 (alpha-diethylaminoacetamido)-quinoline, V

(3) e methoXy-8-(alpha diethylaminoacetamido)- quino1ine. V

(4) 3- methQXy-S-(alpha+diethylaminoacetamido) -quin'oline.

(5)' 2 rhethoxy-l-(alpha-diethylaminoacetamide) -quinoline. v f

(6) 7 ,methozry-fl (alpha-cliethylaminoacetamido) -quinoline. 3

(7) 6 propoxy8-(alpha diethylaminoacetaniido) -quinoline. V a

(8) fi-butoxy 8 (alpha-diethylaminoacetamido) quinoline. H: a

(9) G-roethoxy 7 (alpha-diethylaminoaoetamidmuinolihe (10) 6 methoxy 5 (alnha-diethylaminoaoe'tamido hquinoline. I

(l1) 6 methoxy-e-(alpha-diethylaminoacetamidol quinoline;

(12) 6 methoxy-3-(alphwdiethylagfinoacetamido) -quinoline.

(13)"6 methoxy-2-(alpha diethylaminoacet- 'amirlo) -"quinoline.

(14) amethuxyr-6+:(alphadiethylaminoacetamido) -quinoline.

' (15) 5 -methoxyfl2e'(alpha;dithylaminoacetamido) '-'quin'oline.

.(16) fi-ethoxy 8 (alpha'diisopmpylaminoacetamido) -quih'o'line.

"(17) 6-'e'thoxy 8 (alphamimpmpylaminoacetamido) -quinoline.

(18) 6-ethoxy 8 (alpha-diisobutylaminoacetamido) quinoline.

(19) G-ethoxy 8 (alpha-di-n-amylaminoacetamido) -quinoline.

(20) 6 ethoxy-8-(alpha-piperidylacetamido) quinoline.

(21) 4 methoxy-8-(alpha-diisopropylaminoacetamido) -quino1ine.

(22) 3-methoxy 8 (alpha-diisopropylaminoacetamido) -quino1ine.

(23) 4 methoxy-8-(alpha-di-n-propylaminoacetamido) -quinoline.

(24) 4 meth0xy-8-(alpha-diisobutylaminoacetamido) -quinoline.

(25) 4-methoxy 8 (alpha-di-n-amylaminoacetamido) -quin0line.

(26) 4 methoxy 8 (alpha-piperidylacetamido) -quinoline.

(27) 3 methoxy-8-(alpha-di-n-propylaminoacetamido) -quinoline.

(28) 3-methoxy 8 (alpha-diisobutylaminoacetamido) -quinoline.

(29) 3-ethoxy 8 (alpha-diisobutylaminoacetamido) -quino1ine.

(30) B-methoxy 8 (alpha-diisobutylaminoacetamido) -quin0line.

(31) 3-methoxy 8 (alpha-di-n-amylaminoacetamido) -quino1ine.

(32) 3 methoxy 8 (alpha-piperidylacetamido) -quinoline.

(33) 2 methoxy 8 (alpha-diisopropylaminoacetamiclo) -quinoline.

(34) 2 methoxy 8 (alpha-di-n-propylaminoacetamido) -quinoline.

(35) 2-ethoxy 8 (alpha-diisobutylaminoacetamido) -quinoline.

(36) Z-methoxy 8 (alpha-di-n-amylaminoacetamido) -quinoline.

(37) 2-methoxy 8 (alpha-piperidylacetamido) -quin0line.

(38) 7-methoxy 8 (alpha-diisopropylaminoacetamido) -quin0line.

(39) 7 methoxy 8 (alpha-di-n-propy1-.

aminoacetamido) -quinoline.

(40) 7-methoxy 8 (alpha-diisobutylaminoacetamido) -quino1ine.

(41) 7-methoxy 8 (alpha-di-n-amylaminoacetamido) -quinoline.

(42) 7 ethoxy 8 (alpha-piperidylacetamido) -quinoline.

(43) fi-propoxy 8 (alpha-diisopropylaminoacetamido) -quinoline.

(44) 6-propoxy 8 (alpha-diisobutylaminoacetamido) -quinoline.

(45) 6 propoxy 8 (alpha-piperidylacetamido) -quino1ine.

(46) 6-butoxy 8 (alpha-diisopropylaminoacetamido) -quinoline.

(47) 6 butoxy 8 (alpha-diisobutylaminoacetamido) -quino1ine.

- 5 (50) 6-methoxy 7 (alpha-diis opropylaminoacetamido) -quinoline.

(51)-'- 6-methoxy 5 -(alphawdiisopropylaminoacetamido) -quinoline.

(52) 6 -..vmethoxylrlalphaldiisopropylaminoacetamido)-quinoline.

(53). 6 ethoxy 7 -:(a1pha piperidylacetamido) -quino1ine.

-(54) '6 -:'ethoxy 5 -(al'pha-- pipe'ridylacetamido) -quino1ine.

(55) 6-methoxy 4 (alpha-diisopropylaminoacetamido) -quinoline.

(56) 6 methoxy-3-(alpha-diisopropylaminoacetamido) -quinoline.

(57) G-methoxy 2 (alpha-diisopropylaminoacetamido) -quinoline.

(58) 5 methoxy 6 (alpha diisopropylaminoacetamido) -quinoline.

(59) 6 ethoxy 3 (alpha piperidylacetamido) -quinoline.

(60) 6 methoxy 2 (alpha piperidylacetamido) -quinoline.

(61) 5 ethoxy 6 (alpha-piperidylacetamido) -quino1ine. 30 (62) 6 ethoxy 8 (alpha dicyclohexylaminoacetamido) -quinoline.

(63) 5 methoxy 6 (alpha dicyclopentylaminoacetamido) -quino1ine.

(64) 6 methoxy 8 (alpha-ethyl propyl aminoacetamido) -quinoline.

(65) 6 methoxy 8 (alpha-ethyl-n-butyl aminoacetamido) -quinoline.

(66) 6 methoxy-8-(alpha-n-propyl-n-butylaminoacetamido) -quino1ine.

(67) 6 methoxy 8 (alpha-ethyl isopropyl aminoacetamido) -quino1ine.

(68) 6 methoxy 8 (alpha-ethyl isobutyl aminoacetamido) -quin0line.

(69) G-methoxy 8 (alpha isopropyl isobutylaminocetamido) -quinoline.

(70) G-methoxy 8 (alpha ethyl-n-amylaminoacetamido) -quinoline.

(71) 6-methoxy 8 (alpha ethyl allyl amino- 50 acetamido) -quin0line.

(72) 6 methoxy-8-(alpha ethyl vinyl-aminoacetamido) -quinoline.

(73) 6 meth0xy-8-(alpha ethyl cyclopentyl aminoacetamido) -quinoline.

(74) 6-ethoxy 8 (alpha ethyl propyl aminoacetamido) -quino1ine.

(75) 6-ethoxy-8-(alpha ethyl-n-butyl aminoacetamido) -quinoline.

(76) 6-eth0xy 8 (alpha-n-propyl-n-butylaminoacetamido) -quinoline.

(77) 6 ethoxy 8 (alpha-ethyl-isopropylaminoacetamido) -quino1ine.

(78) 6 ethoxy 8 (alpha-ethyl-isobutylaminoacetamido) -quino1ine.

(79) 6-ethoxy 8 (alpha-isopropyl-isobutylaminoacetamido) -quinoline.

(80) 6 ethoxy 8 (alpha-ethyl-n-amylaminoacetamido) -quino1ine.

(81) 6-ethoxy 8 (alpha-ethyl-allyl-aminoacetamido) -quino1ine.

(82) 6-ethoxy 8 (alpha-ethyl-vinyl-aminoacetamido) -quinoline.

(83) 6-eth0xy 8 (alpha-ethyl-cyclopentyl- 75 aminoacetamido) -quinoline.

IcIaim: B-methoxy 3 alpha-ethyl-n-amyI-amino- FOREIGN PATENTS; acetamido) -quino1ine. u be 4 u y Da e WILLIAM F. BRUCE. 65,110 Germany Oct. 17, 1892 5 OTHER REFERENCES REFERENCES CITED Williams, Chemotherapy of Malaria (Pub- The references are of record m the lished by Lederle Laboratories, N. Y., June 1941), me Of tms patem pp. 81-88 and. 141-143.

UNITED STATES PATENTS 10 Wiselogle, Survey of Antimalarial Drugs,

Number Name Date 1941-1945, vol. II, page 1226 (J. W. Edwards,

2,326,497 Riester et a1 Aug. 10, 1943 Ann Arm, Mich, 1946)- 2,424,063 Shonle et a1 July 15, 1947 Certificate of Correction Patent No. 2,494,083 January 10, 1950 WILLIAM F. BRUCE It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 2, line 43, in the formula, for 0 read 020; column 3, line 8, after 35 mm. insert a comma; column 4, lines 20 and 21, for 33 mm. read 85 mm.; line 47, after halogenoacetamido) and before quinoline insert a hyphen; column 7, line 2,.before alpha insert an opening parenthesis; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 5th day of September, A. D. 1950.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

